Biomedical Engineering Reference
In-Depth Information
made for both approaches but it is essential to have a clear under-
standing of what is to be the control value. When dosing relatively
small animals (versus humans) it is possible that systemic absorption
may produce a contralateral reduction on IOP and this may mask a
drug effect if values in the treated eye are compared to the contra-
lateral untreated eye (which may also decrease). Examples of sys-
temically mediated effects in small animals include bilateral
decreases in IOP with unilateral dosing of timolol and apracloni-
dine in cats and a kappa opioid agonist in monkeys [
84
,
85
,
144
].
In general, in early phase efficacy studies there should be a separate
control group which receives vehicle control and the test article
should be administered to only one eye in the treated group(s).
This allows for the detection of a contralateral reduction in IOP and
avoids potentially discarding an effective compound because it does
not alter IOP in the treated eye relative to the contralateral control
(i.e., it lowers IOP in both eyes roughly equally after unilateral
administration). In subsequent studies bilateral dosing may be
initiated to better mimic the clinical situation or to maximize
systemic exposure to the test article. In general, for statistical
analysis purposes, the “N” in an IOP efficacy study is the animal
and not the eye. In studies with bilateral dosing the data from the
two eyes should be averaged (provided the tonometrist has no
inherent bias in measurements from one side versus the other) to
create a single value for that animal at each time point.
There are several distinct phases in an efficacy study
Acclimation Phase
. This phase typically lasts several days to several
weeks depending on species and the set of animals. It is absolutely
essential that conscious dogs, monkeys, and rats be fully acclimated
to the entire process of tonometry as IOP typically decreases as the
animals become better adjusted to the process. The extent of this
decrease may exceed that of a highly effective ocular hypotensive
drug and must not be underestimated. Rabbits also must be accli-
mated to the process, but they tend to adjust more quickly than
other species. Studies which show a decrease in IOP in the control
groups during the dosing phase typically suffer from a lack of
adequate acclimation and the data in the treatment groups should
be viewed with suspicion.
The animals should be acclimated to the entire process from
start to finish including the room, the table, application of topical
anesthesia, the instrument approaching and touching the eye and
ideally the reward at the end of the procedure. Acclimation typically
begins by allowing the animal to become adjusted to the room, the
handlers, and the table or chair (in the case of nonhuman primates)
without IOP measurements. Positive reinforcement, usually with a
unique and highly desired food treat, is essential. In the author's
experience females tend to acclimate faster than males. The room
5.9 Phases of
an Efficacy Study
